The specific objectives of the present grant proposal are to determine the role of chymotrypsin C (CTRC) in the regulation of digestive enzyme activation and degradation and to investigate the mechanism(s) by which CTRC mutants act as risk factors for chronic pancreatitis in humans. This project forms a part of a broad, long-term research program on the molecular pathomechanism of genetic risk factors associated with human chronic pancreatitis. The studies combine biochemical and cell biological approaches with data obtained from human genetic association studies to formulate a molecular disease model that underlies chronic pancreatitis. According to our working hypothesis chymotrypsin C is an essential regulator of digestive enzyme activation and degradation and mutation-induced defects in this regulatory function predisposes to chronic pancreatitis. An alternative hypothesis will be also explored, which suggests that intracellular misfolding of CTRC mutants would elicit endoplasmic reticulum stress;induce the unfolded protein response and trigger the inflammatory process through activation of nuclear factor ?B. Thus, a direct link might be established between mutations in the CTRC gene and pancreatic inflammation. PUBLIC HEALTH RELEVANCE: The present grant proposal intends to characterize a novel genetic risk factor for chronic pancreatitis, an often debilitating and potentially fatal human disease. We wish to find out why mutations in the digestive enzyme chymotrypsin C can increase the risk of chronic pancreatitis in humans. The results can advance the development of novel diagnostic and therapeutic interventions for human pancreatitis.